Common human cancers have been found to be associated with mutations in dominant and recessive oncogenes including the ras and p53 genes(1-4) and frequently produce mutant oncogene proteins that are uniquely present in the patient's cancer but not in normal cells. These tumor specific proteins could form the basis for highly tumor specific immunotherapy which targets an epitope that is present in each cancer cell and is fundamental to the maintenance of the malignant phenotype. The immune cells responsible for tumor cell killing appear to be major histocompatibility complex (MHC) restricted cytotoxic T lymphocytes (CTL). It is now known that such T cells detect target cells for killing by recognizing short peptide fragments of endogenous proteins that are presented to them by class I MHC molecules on the surface of the target cell. Such naturally presented peptides are found to be 8 or 9 residues long and are generated by endogenous antigen processing of both intracellular and membrane proteins (5-7). We have developed an effective method of peptide vaccination and have produced a CTL line specific for a lung cancer derived mutant human p53. We propose to 1) test a panel of mutant ras and p53 peptides for the ability to produce specific CTL, 2) to optimize positive peptides and vaccination procedures, 3) develop syngeneic animal tumor models expressing the effective mutant oncoproteins, and 4) evaluate anti-tumor efficacy of the optimized vaccination procedures.